Genetic Variant ARHGAP22:p.Ala575Ser (chr10-48450406-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021226.4(ARHGAP22):c.1723G>T(p.Ala575Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A575T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ARHGAP22
NM_021226.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0880

Publications

0 publications found

Variant links:

Genes affected

ARHGAP22 (HGNC:30320): (Rho GTPase activating protein 22) This gene encodes a member of the GTPase activating protein family which activates a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues. The result of these interactions is regulation of cell motility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ARHGAP22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040967822).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021226.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP22	NM_021226.4	MANE Select	c.1723G>T	p.Ala575Ser	missense	Exon 9 of 10	NP_067049.2
ARHGAP22	NM_001256024.2		c.1771G>T	p.Ala591Ser	missense	Exon 9 of 10	NP_001242953.1	Q7Z5H3-2
ARHGAP22	NM_001256025.3		c.1741G>T	p.Ala581Ser	missense	Exon 9 of 10	NP_001242954.1	Q7Z5H3-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP22	ENST00000249601.9	TSL:1 MANE Select	c.1723G>T	p.Ala575Ser	missense	Exon 9 of 10	ENSP00000249601.4	Q7Z5H3-1
ARHGAP22	ENST00000417912.6	TSL:1	c.1771G>T	p.Ala591Ser	missense	Exon 9 of 10	ENSP00000412461.2	Q7Z5H3-2
ARHGAP22	ENST00000477708.6	TSL:1	c.1222G>T	p.Ala408Ser	missense	Exon 1 of 2	ENSP00000422868.1	D6R9V6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1415168

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32198

American (AMR)

AF:

0.00

AC:

AN:

38392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25300

East Asian (EAS)

AF:

0.00

AC:

AN:

36654

South Asian (SAS)

AF:

0.00

AC:

AN:

80764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089262

Other (OTH)

AF:

0.00

AC:

AN:

58564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0060

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.022

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.62

M_CAP

Benign

0.017

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.14

PhyloP100

-0.088

PrimateAI

Benign

0.24

PROVEAN

Benign

0.14

REVEL

Benign

0.026

Sift

Benign

0.99

Sift4G

Benign

0.99

Polyphen

0.014

Vest4

0.066

MutPred

0.23

Gain of glycosylation at A575 (P = 0.0017)

MVP

0.16

MPC

0.15

ClinPred

0.042

GERP RS

-8.3

Varity_R

0.034

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over